The present invention relates to the use of radiation, preferably near-infrared radiation to detect and measure the concentration of constituents or other properties of interest of a material. More particularly, apparatus and methods have been developed for measurement of the concentration of constituents such as hemoglobin and its variants and derivatives, glucose, cholesterol and its combined forms, drugs of abuse, and other analytes of clinical and diagnostic significance in a non-invasive manner.
Because the apparatus developed for use of this method does not require the withdrawal of blood in order to perform these measurements, it is particularly suitable for testing in the home on a chronic basis such as for glucose levels in diabetics and for kidney function, e.g., urea or creatinine testing, in patients undergoing home dialysis. The present invention uses a variety of methods to change the pathlength through tissue and/or the blood volume within an optically sampled tissue to help distinguish the desired signal produced by one or more components of the blood volume from background noise produced by tissue or other components of the blood volume and from the background noise of the system itself.
The development of clinical testing procedures that do not require the withdrawal of blood has become an important goal due to the spread of AIDS and the associated fears among the public and health care personnel. Along with AIDS, other diseases, such as hepatitis, can be spread through the use of invasive procedures without stringent precautions to assure sterility. "Nosocomial transmission of hepatitis B virus associated with the use of a spring-loaded finger-stick device," New England Journal of Medicine. 326(1 1), 721-725 (1992), disclosed a hepatitis mini-epidemic in a hospital caused by the improper use of an instrument for obtaining blood samples. The article describes how the hospital personnel unintentionally transmitted the virus from patient to patient by misuse of the sampling device. Such transfers, potentially hazardous to health care personnel as well as to patients, are eliminated by the non-invasive testing method performed by the apparatus and method of the invention.
Non-invasive testing will become particularly effective in the long-term management of diabetes. Improperly controlled glucose levels in diabetics can result in damage to the circulatory system, the nervous system, the retina and other organs. This damage can be largely eliminated by more effective control of glucose levels. However, this level of control requires the measurement of glucose levels four or more times a day. With current apparatus and methods, a painful finger prick is required for each such measurement. Furthermore, that part of the apparatus that contacts the blood to produce the required chemical change used in the measurement is disposed of after each measurement. The cost of these disposables can run thousands of dollars per year. The inconvenience and discomfort of glucose measurement exacts a further psychological toll from the diabetic. Finally, because the sampling process is conducted by relatively untrained personnel, it is prone to error. These errors have been reported to be as high as three to five times the inherent error in the process. Errors in the sampling process can occur either as a result of failure to obtain a proper blood sample (e.g., the sample may be an admixture of intracellular or interstitial fluid or blood) or failure to correctly apply the sample to the disposable part of the apparatus, or both.
These deficiencies in currently available apparatus and methods have caused a number of groups to attempt to develop devices for non-invasively measuring concentrations of various blood constituents. The most commercially successful devices for the non-invasive measurement of chemical constituents of blood are those that use "pulse oximetry" to measure the relative concentrations of oxyhemoglobin and deoxyhemoglobin. Because these two constituents are both highly absorptive in the near infrared and because of their crossing broadband features, the ratio of radiation intensities at two wavelengths can provide the requisite information. Based in part on the success of hemoglobin ratio measurements, much current work on non-invasive concentration measurements for chemical constituents of blood has also used the near-infrared region of the electromagnetic spectrum. Because of the number of diabetics most of this research is directed to techniques for the non-invasive measurement of blood glucose levels. Although glucose is present in low concentration, and although glucose has low absorptivity, the wavelength band between 700 nm and 1100 nm contains the third overtones of the glucose absorption spectrum. This band theoretically allows minimization of interference due to water absorption and exhibits good penetration of human tissue. Other promising research has used longer wavelengths, from 1100 nm to about 2500 nm.
Substantially all of this work has been carried out using variants on classic spectrophotometric methods. Classical methods typically use detectors which measure the radiation transmitted through or reflected from the sample in a relatively narrow wavelength passband. The passband is kept narrow for several reasons. First, a narrow passband reduces the practical deviations that can occur relative to the theoretical relationships between constituent concentration and absorbance. Second, a narrow detector passband allows better measurement of sharply peaked spectra by providing a measurement closer to the spectral peak of the constituent of interest. According to classical methods, this improves specificity, and for full-spectrum measurements, provides a more faithful rendition of the absorbance or reflectance spectrum.
The wavelength passband within which the detector operates can either be a property of the source or can be obtained by placement of an appropriate filter between the source and the sample, between the sample and the detector, or both. The width of the passband in classic spectrophotometry is ordinarily chosen to be small relative to the width of the spectral features of the constituent of interest and of the sample. Typically, a passband half-width of less than 10% of the spectral half-width is recommended.
In some spectrophotometric devices, the source is designed to scan the spectral region of interest so that the measured wavelength varies with time in a controlled manner. In other cases, the source is transformed into a coded broadband source whose interaction with the sample is later decomposed into narrow-band responses.
In most classic spectrophotometric devices and methods, the measured data is initially in the form of an uncorrected intensity versus wavelength. The next important step, performed within the spectrophotometric apparatus, is a logarithmic conversion of the data into absorbance or reflectance units using some reference intensity versus wavelength data for normalization. Extensive data processing of the transformed data is then employed in an attempt to isolate the components of the data arising from the constituent(s) of interest from the components arising from the background (due to constituents that are not of interest and instrumental artifacts). Many techniques are available for this isolation, virtually all of which are based on statistical regression techniques. Examples of this general approach include the works of Rosenthal, U.S. Pat. No. 5,023,737, and of Clarke, U.S. Pat. No. 5,054,487.
All of these classical spectrophotometric methods essentially search for a unique response or pattern of responses due to the constituent of interest at one or more specific wavelengths (or narrow wavelength passbands) and then attempt to separate these effects from the effects due to background constituents at those same narrow wavelength passbands. However, glucose and many other constituents of interest possess only weak broadband spectral features in the wavelength ranges of interest. Furthermore, the measurement environment is generally a mixture containing glucose and many other constituents having overlapping but different broadband spectral structures several of which, including water and the hemoglobin species, are strong absorbers in the wavelength ranges of interest. In non-invasive clinical measurements, these problems are further compounded by the presence of multiple diffuse radiation scattering centers in the tissue. As a result, the overall measurement environment is not conducive to the use of classical spectrophotometric techniques.
U.S. Pat. No. 5,321,265 (the "Block '265 patent") discloses a system having a plurality of filters with overlapping passbands analogous to the overlapping passbands of the human eye's photoreceptors. The disclosed methods and devices use a broadband radiation source to illuminate a sample held in a chamber. Radiation from the broadband source is passed through a plurality of spectrally overlapping filters before reaching the detectors. These detectors detect the radiation transmitted, reflected or emitted from the sample and thereby measure the sample's "color" in the region of the spectrum defined by the filter and detector responses. U.S. Pat. No. 5,434,412 (the "Sodickson '412 Patent") and U.S. Pat. No. 5,424,545 (the "Block '545 Patent") concern modifications to the basic devices and methods disclosed in Block '265 to achieve better results.
The present invention concerns additional methods and devices which may be employed toward the measurement of a sample's color in pulse oximetry, and in standard photometric and spectrophotometric measurements for in vivo systems. The methods and devices of the invention are all directed to the use of mechanical stimuli for improving the accuracy, sensitivity, and repeatability of non-invasive measurements of blood constituents such as glucose. This is achieved in the invention by the use of mechanical stimuli to increase the optical magnitude of normal cardiac pulses, to generate a change in volume either within the blood or within the extra-cellular and intra-cellular compartments of the tissue, or to provide an estimate of tissue scattering.
The use of mechanical stimuli to enhance the signal-to-background ratio in pulse oximetry is well known. First, the measurement of the pulsatile portion of the data segregates the response of the blood from the interfering background response of the tissue lying in the optical path. Second, since only the arterial component of blood volume changes with each pulse, pulsatile measurement further segregates the arterial blood response from the venous blood response. This is particularly significant in pulse oximetry since arterial blood is considerably more saturated with oxygen than venous blood.
The use of mechanical stimuli, in the form of direct pressure, has long been considered essential in the non-invasive measurement of blood pressure. Its use in pulse oximetry applications has been considered for a number of years. For example, Wood (see U.S. Pat. No. 2,706,927) suggests that signal characteristics might be improved by squeezing the earlobe to remove the blood and then restoring blood flow after the measurement. Similarly, Shiga and Suzaki (U.S. Pat. No. 4,927,264) suggest using a pressure of approximately diastolic pressure in pulse oximetry. Both groups however, used the pressure for measurement of hemoglobin ratios in venous blood only. In fact, Shiga et al. specifically made their arterial measurements without applied pressure. Many of the pulse oximetry instruments on the market (for example, Nellcor, Pleasanton, Calif.; Novametrix, Wallingford, Conn.) maintain mild, steady pressure on the skin near the measurement site. However, there is no active use of the applied pressure in generating improved data.
In other disclosures, Harjunmaa et al. see U.S. Pat. Nos. 5,178,142 and 5,183,042 and Mendelson et al. see U.S. Pat. No. 5,372,135 demonstrate the possibility of compressing tissue to either change the volume of venous blood in the tissue or to change the ratio of intracellular to extracellular fluid volume. However, none of these disclosures demonstrate active control over the cardiac pulse to generate a change in arterial blood volume with improved properties for use in generating improved photometric data, nor do they indicate the possibility of creating controllable pulsatile variations in tissue optical characteristics to improve the measurement of such characteristics. Finally, Kiani-Azarbayjany et al. (U.S. Pat. No. (5,638,816) discloses that a pressure-induced pulse, separate from that of the cardiac cycle, may be used to alter blood volume and thereby increase signal-to-background ratio. However, this disclosure does not disclose methods of applying constant pressure for amplifying the normal cardiac pulse, nor does it reveal the superior methods disclosed herein for inducing the non-cardiac pulse.
For in vivo measurement of materials which have a much lower concentration or which provide a much lower signal, such as glucose, the natural pulsatile modulation, which is much lower in amplitude than the total signal, may be so small as to be useless. This is particularly likely for classical spectrophotometric measurements which have very low signal-to-background ratios when the concentration of the constituent of interest is low.
Accordingly, an object of the invention is to provide methods of using controlled mechanical stimuli to improve the signal-to-background ratio of in vivo non-invasive optical measurement devices.
A further object of the invention is to utilize controlled mechanical stimuli to improve methods for measuring the concentrations of constituents in arterial blood non-invasively.
A still further object of the invention is to generate improved artificial pulses to obtain greater sensitivity in non-invasive optical measurements.
Another object of the invention is to provide a measure of tissue scattering at a measurement site.
These and other objects and features of the invention are achieved by the methods and apparatus described in the Summary of the Invention, the Detailed Description and the Drawing.